The citation of references herein shall not be construed as an admission that such is prior art to the present invention.
Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic myeloproliferative disorders characterized by monoclonal plasma cell proliferation. It is estimated that approximately 5% of the population above the age of 50 is affected by plasma cell dyscrasias [Kyle et al. N Engl J Med 354, 1362-1369, 2006]. Both conditions consistently precede multiple myeloma (MM), an incurable malignancy of terminally differentiated B cells, with recent studies demonstrating that these conditions represent one disease on a disease spectrum [Landgren. Hematology Am Soc Hematol Educ Program 2010, 295-302]. For patients with MGUS or SMM, the lifetime risk of progression to MM is estimated to be 15-59% [Perez-Persona et al. Blood 110, 2586-2592, 2007]. Consequently, MGUS and SMM patients require indefinite follow-up. Currently there is no accepted prevention or treatment strategy available for either condition—patients simply undergo continuous monitoring of plasma markers [Kumar. Cancer Treat Rev 36 Suppl 2, S3-11].
Once MM develops, patients typically receive the proteasome inhibitor bortezomib (BTZ) as first line treatment. BTZ has demonstrated remarkable response rates in both relapsed and newly diagnosed MM. By virtue of inhibiting the proteasome, BTZ causes accumulation of misfolded proteins in the endoplasmic reticulum (ER) and activation of the unfolded protein response (UPR), which culminates in induction of caspase 12-mediated apoptosis [Chari et al. Biologics 4, 273-287, 2010]. An expansive, well developed rough ER highly specialized for the constant synthesis and secretion of large amounts of protein, namely immunoglobulin (Ig), is a defining characteristic of plasma cells. The innate biology of this class of cells is believed to account for the exquisite sensitivity of plasma cell disorders to agents like BTZ which target ER stress related signaling pathways to induce apoptosis.
Given the clinically validated importance of targeting ER stress pathways in the treatment of MM and the biological similarities that exist between SMM and MM [Shah et al. Leukemia 23, 1964-1979, 2009], BTZ is also predicted to be effective in the management of MGUS and/or SMM. However, BTZ carries the potential for serious side effects; for example, more than 30% of the patients receiving BTZ treatment develop painful peripheral neuropathy [Cavaletti. Lancet Oncol 12, 120-121]. In fact, Takeda Pharmaceuticals recently received FDA approval for administration of BTZ by subcutaneous injection in an effort to reduce the number of patients experiencing severe nerve damage. It is expected that this will become the preferred route of administration. This route of administration, however, along with the potential for harmful side effects, precludes BTZ from being used in the treatment of MGUS/SMM.